Signal transduction from toll-like receptors (TLRs) is important for innate immunity against infections, but deregulated TLR signaling contributes to inflammatory disorders. Here we show that myeloid cell-specific ablation of TRAF2 greatly promotes TLR-stimulated proinflammatory cytokine expression in macrophages and exacerbates colitis in an animal model of inflammatory bowel disease. TRAF2 deficiency does not enhance upstream signaling events, but it causes accumulation of two transcription factors, c-Rel and IRF5, known to mediate proinflammatory cytokine induction. Interestingly, TRAF2 controls the fate of c-Rel and IRF5 via a proteasome-dependent mechanism that also requires TRAF3 and the E3 ubiquitin ligase cIAP. We further show that TRAF2 also regulates inflammatory cytokine production in tumor-associated macrophages and facilitates tumor growth. These findings demonstrate an unexpected anti-inflammatory function of TRAF2 and suggest a proteasome-dependent mechanism that limits the proinflammatory TLR signaling.

Tumor cells of colorectal cancer (CRC) release exosomes into the circulation. These exosomes can mediate communication between cells and affect various tumor-related processes in their target cells. We present a quantitative proteomics analysis of the exosomes purified from serum of patients with CRC and normal volunteers; data are available via ProteomeXchange with identifier PXD003875. We identified 918 proteins with an overlap of 725 Gene IDs in the Exocarta proteins list. Compared with the serum-purified exosomes (SPEs) of normal volunteers, we found 36 proteins upregulated and 22 proteins downregulated in the SPEs of CRC patients. Bioinformatics analysis revealed that upregulated proteins are involved in processes that modulate the pretumorigenic microenvironment for metastasis. In contrast, differentially expressed proteins (DEPs) that play critical roles in tumor growth and cell survival were principally downregulated. Our study demonstrates that SPEs of CRC patients play a pivotal role in promoting the tumor invasiveness, but have minimal influence on putative alterations in tumor survival or proliferation. According to bioinformatics analysis, we speculate that the protein contents of exosomes might be associated with whether they are involved in premetastatic niche establishment or growth and survival of metastatic tumor cells. This information will be helpful in elucidating the pathophysiological functions of tumor-derived exosomes, and aid in the development of CRC diagnostics and therapeutics.

Osteoporosis is characterized by a decrease in bone mass and strength, rendering people prone to osteoporotic fractures caused by low-energy forces. The primary treatment strategy for osteoporotic fractures is surgery; however, the compromised and comminuted bones in osteoporotic fracture sites are not conducive to optimum reduction and rigid fixation. In addition, these patients always exhibit accompanying aging-related disorders, including high inflammatory status, decreased mechanical loading and abnormal skeletal metabolism, which are disadvantages for fracture healing around sites that have undergone orthopedic procedures. Since the incidence of osteoporosis is expected to increase worldwide, orthopedic surgeons should pay more attention to comprehensive strategies for improving the poor prognosis of osteoporotic fractures. Herein, we highlight the molecular basis of osteoimmunology and bone mechanosensation in different healing phases of elderly osteoporotic fractures, guiding perioperative management to alleviate the unfavorable effects of insufficient mechanical loading, high inflammatory levels and pathogen infection. The well-informed pharmacologic and surgical intervention, including treatment with anti-inflammatory drugs and sufficient application of antibiotics, as well as bench-to-bedside strategies for bone augmentation and hardware selection, should be made according to a comprehensive understanding of bone biomechanical properties in addition to the remodeling status of osteoporotic bones, which is necessary for creating proper biological and mechanical environments for bone union and remodeling. Multidisciplinary collaboration will facilitate the improvement of overall osteoporotic care and reduction of secondary fracture incidence.

Lysosomes perform a range of functions, some of which, such as degradation, are common to all cell types. Others, such as secretion or lysosomal exocytosis, are more specialised and tend to involve fusion of this organelle with the cell surface to release its contents. This review describes lysosomal regulation of the inflammatory glucocorticoid signaling pathways, and summarizes the roles of lysosomes in negatively or positively modulating the production of inflammatory cytokines. We also review the characteristic changes in lysosomal hydrolases and membrane proteins in common autoimmune diseases. Finally, future directions in lysosome research are proposed, with it being suggested that the role of lysosomes will continue to be of growing interest in immunity research.

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